Xylopic acid (XA) is an isolate of a Ghanaian traditional spice, Xylopia aethiopica. This spice is used locally for the treatment of various conditions including pain -rheumatism, headache, neuralgia and colic pain. In this study, xylopic acid was investigated for the possibility of causing tolerance or dependence when administered alone or in combination with morphine. Adult male Sprague-Dawley rats (200-250 g) received xylopic acid (10-100 mg/kg, p.o.) or morphine (10 mg/kg, i.p.) twice daily for 14 days to induce analgesic tolerance. To develop dependence, another group of rats were given escalating doses of xylopic acid (10-300 mg/kg) or morphine (2.5-40 mg/kg, i.p.) for 7 days. To determine the effect of xylopic acid on the development of morphine tolerance and dependence, xylopic acid (10-100 mg/kg) was administrated orally before morphine. The tail-withdrawal assay and naloxone precipitation test were used to assess the extent of tolerance and dependence, respectively. Rats that received chronic morphine administration displayed tolerance to its analgesic effect and developed morphine dependence. Xylopic acid (10-100 mg/kg) significantly (p<0.001) prevented the development of morphine tolerance. Additionally, xylopic acid inhibited some naloxone-induced withdrawal signs (weight loss, diarrhoea and jumping). Chronic administration of xylopic acid did not produce tolerance or dependence. The inhibitory effect of XA on withdrawal jumps in morphine-dependent mice was blocked by pretreatment with a2-adrenoceptor antagonist, yohimbine, but not by a1-adrenoceptor antagonist, prazosin. The membrane expression of a2A-adrenoceptors in the brainstem was decreased in morphine withdrawn animals. The reduction was prevented by repeated administration of XA. These results suggest that XA inhibits morphine tolerance and dependence, and this is due partly to the prevention of the decreased membrane expression of the a2A-adrenoceptor in the brainstem.

Traditionally, Xylopia aethiopica is used to manage pain disorders such as neuralgia, colic pain, rheumatism and headache. Using animal models, this study aimed to investigate the ability of Xylopic Acid (XA), a kaurene diterpene obtained from Xylopia aethiopica, to cause tolerance when administered alone or combined with morphine. Development of withdrawal symptoms on discontinuation was also investigated. Tolerance to morphine was induced in rats through an 8-day regimen of chronic administration of morphine (10 mg/kg; twice daily). Effects of XA alone (100 mg/kg) or XA (10-100 mg/kg) on morphine tolerance and withdrawal syndrome precipitated with naloxone hydrochloride (3 mg/kg) were also assessed. XA's mechanism of action was then explored through drug-receptor binding.Chronic morphine administration in rats resulted in analgesic tolerance and morphine withdrawal syndrome. Chronic XA administration did not result in tolerance to XA's antinociceptive effect. Development of morphine withdrawal syndrome precipitated by naloxone and morphine tolerance was significantly (F(12, 60)=29.88, p<0.0001) inhibited by XA. Xylopic acid inhibited development of diarrhea, jumps and weight loss. Pretreatment with α-2-adrenoceptor antagonist, yohimbine, 5HT3 antagonist, ondansetron and muscarinic antagonist, atropine, significantly (p=0.0042) blocked the inhibitory effect of XA on withdrawal jumps. Pretreatment with naloxone produced similar effects on withdrawal jumps as XA alone. Drug-receptor binding assays revealed a lack of significant interaction of XA on alpha-2 adrenoceptors (A, B, C) but exhibited significant DOR-selective antagonism similar to naltrindole. This study reveals that xylopic acid significantly inhibits morphine antinociceptive tolerance and withdrawal in rats. This is the first report of xylopic acid's antagonism on delta opioidergic receptors and potential as an inhibitor of chronic morphine tolerance.